Biodegradable polymer formulations

ABSTRACT

A polymeric material which can degrade in less than 6 months is provided. The polymeric material includes a plurality of biodegradable polymers having a polydispersity or molecular weight distribution from about 1.5 to about 2.5. A method of making the polymeric material is also provided. The method includes mixing a plurality of biodegradable polymers together to form a polymeric mixture, wherein the polymeric mixture has a polydispersity from about 1.5 to about 2.5. The application of this polymeric material to medical devices such as and implantable depots is described. A method for treating acute pain in an organism to reduce, prevent or treat pain utilizing these polymeric materials having a polydispersity or molecular weight distribution from about 1.5 to about 2.5 is also provided.

This application claims the benefit of the filing date of and is acontinuation-in-part of U.S. application Ser. No. 14/286,673, filed May23, 2014, entitled “Methods for Preparing Polymers Having Low ResidualMonomer Content”, which is a continuation of U.S. application Ser. No.13/462,395, filed on May 2, 2012, now U.S. Pat. No. 8,735,504. Theseentire disclosures are hereby incorporated by reference into the presentdisclosure.

BACKGROUND

Drugs may be delivered to patients by a variety of methods includingoral, intravenous, intramuscular, inhalation, topical, subcutaneousdelivery or delivery directly or locally to the treatment site (e.g.,intrathecally, intraspinally, intraarticularly, etc.). The method ofdelivery chosen depends, among other things, upon the condition beingtreated, desired therapeutic concentration of the drug to be achieved inthe patient and the duration of drug concentration that must bemaintained.

Localized delivery of therapeutic agents has become increasingly morepopular over the years because it has several advantages over moreconventional routes of drug delivery such as oral delivery. Localizeddelivery has the advantage of allowing the therapeutic agent to beimplanted directly at the site where drug action is needed. This becomesespecially important for drugs that have unwanted systemic side effects.

Localized delivery of therapeutic agents has the advantage of protectingthe therapeutic agent from breakdown due to harsh physiologicalenvironments (e.g., gastric and liver enzymes) and thus improves thedrug's stability in vivo. This particular feature makes this technologyparticularly attractive for the delivery of labile drugs such asproteins and peptides. Localized delivery also improves patientcompliance. For example, therapeutic agents can be encapsulated anddelivered locally allowing the drug to be released over extended periods(e.g., 6 months or longer) and hence eliminates the need for multipleinjections. This feature can improve patient compliance especially fordrugs for chronic indications, requiring frequent injections.

In the past, localized repeat delivery of therapeutic agents has beenused to treat chronic debilitating diseases such as osteoarthritis.Osteoarthritis is a chronic condition that affects millions of people inthe world, and it is a type of arthritis that is caused by the chronicbreakdown and eventual loss of cartilage in one or more joints.Osteoarthritis often affects synovial joints, such as the knees, hips,fingers, thumbs, neck, and spine. Severe forms of the disease areextremely disabling and restrict a patient's lifestyle. Localizeddelivery via. intraarticular injection of corticosteroids, hyaluronan orhylan provides some short term relief in controlling the pain symptomsof osteoarthritis.

Sciatica, another debilitating disease, can be a painful conditionassociated with the sciatic nerve which runs from the lower part of thespinal cord (the lumbar region), down the back of the leg and to thefoot. Sciatica generally begins with a herniated disc, which later leadsto local immune system activation. The herniated disc also may damagethe nerve root by pinching or compressing it, leading to additionalimmune system activation in the area. In the past, localized delivery ofcorticosteroids (e.g., epidural) has been used to provide short termrelief of the inflammation and pain associated with sciatica.

Newer methods are currently being investigated for treatment of chronicdebilitating diseases utilizing localized delivery of drug depots forrelease at various release rates. In these treatments typically the drugdepot is delivered locally to the treatment site and the drug isreleased from the depot in a relatively uniform dose over weeks, monthsor even years. Localized delivery of drug depots is becoming especiallyimportant and popular in modulating the immune, inflammation and/or painresponses in treatment of chronic diseases.

The slow degradation of polymers often limits their performance inmedical device applications. Making biomedical devices involves the useof a broad variety of polymers. Many devices need biodegradablepolymers. For example, polylactides can be used for degradableorthopedic rods, screws and plates as well drug delivery products, forexample, implantable depots. Biodegradable polymers for tissueengineered drugs containing implantable depots may need to degrade anddisappear after the drugs are released.

Sometimes after the drug depot is implanted at the treatment site,unfortunately, the drug depot may migrate from the implant site asphysiological conditions change (e.g., repair and regeneration of cells,tissue in growth, and movement at implant site, etc.). At times, thismay reduce efficacy of the drug as the drug depot migrates away from theimplant site and lodges in a distant site. If this occurs, often thedrug depot will have to be removed from the distant site and bereinserted causing additional physical and psychological trauma to apatient. In some cases, if the drug depot migrates into a joint, thedrug depot may inhibit movement. In more severe cases, if the drug depotmigrates in a blood vessel, it may restrict blood flow causing anischemic event (e.g., embolism, necrosis, infarction, etc.), which couldbe detrimental to the patient.

Therefore, new drug depot compositions and methods are needed, which canallow not only for accurate and precise placement of a drug depot withminimal physical and psychological trauma to a patient, but also providevarious rates of degradation to release drug at the desired rate anddegrade in time.

SUMMARY

Polymeric materials are provided comprising a plurality of biodegradablepolymers having a polydispersity index or molecular weight distributionfrom about 1.5 to about 2.5. in some embodiments, the polymericmaterials have a polydispersity index of greater than 2.

In some embodiments, it is contemplated that the polymeric materialscomprise, consist essentially of, or consist of a polymeric mixture orblend of a first polymer in an amount of about 10%, a second polymer inan amount of about 20%, a third polymer in an amount of about 50% and afourth polymer in an amount of about 20%. In other embodiments, theplurality of biodegradable polymers comprises a first polymer in anamount from about 5% to about 15%, a second polymer in an amount ofabout 15% to about 25%, a third polymer in an amount of about 45% toabout 55% and a fourth polymer of about 15% to about 25% by weight.

In some embodiments, the polymeric materials comprise, consistessentially of, or consist of a polymeric mixture or blend of a firstpoly(D,L-lactide) having an inherent viscosity from about 0.15 to about0.25 dL/g and ester end groups in an amount of about 10%, a secondpoly(D,L-lactide) having an inherent viscosity from about 0.40 to about0.50 dL/g and carboxylic acid end groups in an amount of about 20%, athird poly(D,L4actide) having an inherent viscosity from about 0.40 toabout 0.50 dL/g and ester end groups in an amount of about 50% and afourth poly(D,L-lactide) having an inherent viscosity from about 0.60 toabout 0.80 dL/g and ester end groups in an amount of about 20%.

Compositions and methods are provided comprising clonidine or itspharmaceutically acceptable salts that are administered in order totreat pain and/or inflammation. The compositions and methods may, forexample, be used to treat pain due to a spinal disc herniation (i.e.,sciatica), spondilothesis, stenosis, osteoarthritis, carpal/tarsaltunnel syndrome, tendonitis, temporomandibular joint disorder (TMJ),discogenic back pain, joint pain or inflammation.

In some embodiments, there is an implantable medical device for reducingor treating pain in a patient in need of such treatment, the implantablemedical device comprising clonidine in an amount from about 1.0 wt. % toabout 20 wt. % of the implantable medical device, and a plurality ofbiodegradable polymers having a polydispersity index greater than 2,wherein the implantable medical device can degrade and disappear in lessthan 6 months.

In other embodiments, there is an implantable drug depot for treatingchronic pain in a patient in need of such treatment, the implantablemedical device comprising clonidine hydrochloride in an amount fromabout 0.01 wt. % to about 20 wt. % of the implantable drug depot, and aplurality of biodegradable polymers comprising poly (D-lactide), poly(D,L-lactide), poly (L-lactide) wherein the implantable drug depotreleases the clonidine over a period of at least 30 days to less than 6months and the plurality of biodegradable polymers degrade and disappearin less than 6 months.

In some embodiments, there is a method for treating chronic pain in apatient in need of such treatment, the method comprising administeringto a target tissue site beneath the skin of the patient an implantabledrug depot comprising a plurality of biodegradable polymers having apolydispersity index of greater than 2, the implantable drug depotdegrading an disappearing in less than 6 months.

In some embodiments, the drug depot may: (i) consist of only theclonidine (or one or more of its pharmaceutically acceptable salts) andthe plurality of biodegradable polymers having a polydispersity greaterthan 2; or (ii) consist essentially of the clonidine (and/or one or moreof its pharmaceutically acceptable salts) and the plurality ofbiodegradable polymers having a polydispersity greater than 2; or (iii)comprise the clonidine (and/or one or more of its pharmaceuticallyacceptable salts), and the biodegradable polymer(s) and one or moreother active ingredients, surfactants, excipients or other ingredientsor combinations thereof.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

Reference will now be made in detail to certain embodiments of theinvention. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

An implantable medical device includes that the device can be implantedinto the human body. In various embodiments, the medical device is notimplanted into the eye. The medical device allows release of the drug ortherapeutic agent. A medical device includes a drug depot, which can besolid, semi-solid or in gel form.

The term “implantable” as utilized herein refers to a biocompatibledepot (e.g., device) retaining potential for successful placement withina mammal. The expression “implantable depot” and expressions of the likeimport as utilized herein refers to an object implantable throughsurgery, injection, or other suitable means whose primary function isachieved either through its physical presence or mechanical properties.

A “drug depot” is the composition in which a drug or activepharmaceutical ingredient is administered to the body. Thus, a drugdepot may comprise a physical structure (e.g., strip, pellet) tofacilitate implantation and retention in a desired site (e.g., a discspace, a spinal canal, a tissue of the patient, particularly at or neara site of chronic pain, etc.). The drug depot may also comprise the drugitself The term “drug” as used herein is generally meant to refer to anysubstance that alters the physiology of a patient. The term “drug” maybe used interchangeably herein with the terms “therapeutic agent,”“therapeutically effective amount,” and “active pharmaceuticalingredient” or “API.” It will be understood that unless otherwisespecified a “drug” formulation may include more than one therapeuticagent, wherein exemplary combinations of therapeutic agents include acombination of two or more drugs. The drug provides a concentrationgradient of the therapeutic agent fur delivery to the site. In variousembodiments, the drug depot (e.g., fiber) provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.01 cm to about 20 cm from the administration site and comprisesclonidine. A drug depot may also include a pump or pellet.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain or spasticity, improvement in the condition throughmuscle relaxation, etc. The dosage administered to a patient can be assingle or multiple doses depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired, in some embodiments theformulation is designed for immediate release. In other embodiments theformulation is designed for sustained release. In other embodiments, theformulation comprises one or more immediate release surfaces and one ormore sustained release surfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof. In some embodiments, thedrug depot has a modulus of elasticity in the range of about 1×10² toabout 6×10⁵ dyn/cm², or 2×10⁴ to about 5×10⁵ dyn/cm², or 5×10⁴ to about5×10⁵ dyn/cm².

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot can break down ordegrade within the body to non-toxic components after or while atherapeutic agent has been or is being released. Generally, the term“biodegradable polymer” means a synthetic or a naturally derivedbiodegradable, biocompatible polymer that may be absorbed (resorbed)once implanted in a living mammalian body. In the present applicationbiodegradable polymer refers to synthetically derived polymers.Synthetic biodegradable polymers include, but are not limited to,polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyorthoester(POE), polylactic acid (PLA), polyglycolic acid (PGA),polyactic-glycolic acid (PLGA), D-lactide, D,L-lactide co-caprolactone,L-lactide-co-caprolactone, D,L-lactide-co-glycolide-co-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D,L-lactide),poly(L-lactide), poly(esteramide) or a combination thereof. Suitablepolymers that can be used in the present application are described inU.S. application Ser. No. 13/462,395, filed on May 2, 2012, now U.S.Pat. No. 8,735,504. The entire disclosure is hereby incorporated byreference into the present disclosure.

By “bioerodible” it is meant that the depot will erode or degrade overtime due, at least in part, to contact with substances found in thesurrounding tissue, fluids or by cellular action. By “bioabsorbable” itis meant that the depot will be broken down and absorbed within thehuman body, for example, by a cell or tissue. “Biocompatible” means thatthe depot will not cause substantial tissue irritation or necrosis atthe target tissue site.

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in viva of the drug depot,or a fiber or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same fiber. In various embodiments, thesustained release and immediate release may be part of separate drugdepots. For example a bolus or immediate release formulation ofclonidine may be placed at or near the target site and a sustain releaseformulation may also be placed at or near the same site. Thus, evenafter the bolus becomes completely accessible, the sustain releaseformulation would continue to provide the active ingredient for theintended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-four toseventy-two hours after implantation. “Initial burst” or “burst effect”“burst release” or “bolus dose” refers to the release of therapeuticagent from the depot (e.g., fiber, pellet, strip, etc.) during the firsttwenty-four hours to seventy-two hours after the depot (e.g., fiber)comes in contact with an aqueous fluid (e.g., interstitial fluid,synovial fluid, cerebral spinal fluid, etc.). The “burst effect” isbelieved to be due to the increased release of therapeutic agent fromthe drug depot. In some embodiments, the drug depot has one or moreburst release surfaces that releases about 10%, 15%, 20%, 25%, 30%, 35%,45%, to about 50% of the drug over 24 or 48 hours.

In alternative embodiments, the drug depot is designed to avoid orreduce this initial burst effect (e.g., by applying an outer polymercoating to the drug depot).

“Treating” or “treatment” of a disease or condition refers to executinga protocol that may include administering one or more drugs to a patient(human, other normal or otherwise or other mammal), in an effort toalleviate signs or symptoms of the disease or condition. Alleviation canoccur prior to signs or symptoms of the disease or condition appearing,as well as after their appearance. Thus, treating or treatment includespreventing or prevention of disease or undesirable condition. Inaddition, treating or treatment does not require complete alleviation ofsigns or symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain and/or inflammation” includes a decrease in pain and/orinflammation and does not require complete alleviation of pain and/orinflammation signs or symptoms, and does not require a cure. In variousembodiments, reducing pain and/or inflammation includes even a marginaldecrease in pain and/or inflammation. By way of example, theadministration of the effective dosage of clonidine may be used toprevent, treat or relieve the symptoms of pain and/or inflammation fordifferent diseases or conditions. These disease/conditions may comprisepost-operative pain, oral-facial diseases, bursitis, tendonitis, chronicinflammatory diseases, including, but not limited to autoimmunediseases, such as multiple sclerosis, rheumatoid arthritis,osteoarthritis, insulin dependent diabetes (type I diabetes), systemiclupus erythrematosis and psoriasis, immune pathologies induced byinfectious agents, such as helminthic (e.g., leishmaniasis) and certainviral infections, including HIV, and bacterial infections, includingLyme disease, tuberculosis and lepromatous leprosy, tissue transplantrejection, graft versus host disease and atopic conditions, such asasthma and allergy, including allergic rhinitis, gastrointestinalallergies, including food allergies, eosinophilia, conjunctivitis orglomerular nephritis. In some embodiments, the drug depot containing thetherapeutic agent is not administered in, to or near the eye.

One chronic condition is sciatica. In general, sciatica is an example ofpain that can transition from acute to neuropathic pain. Sciatica refersto pain associated with the sciatic nerve which runs from the lower partof the spinal cord (the lumbar region), down the back of the leg and tothe foot. Sciatica generally begins with a herniated disc. The herniateddisc itself leads to local immune system activation. The herniated discalso may damage the nerve root by pinching or compressing it, leading toadditional immune system activation in the area. In various embodiments,the clonidine may be used to reduce, treat, or prevent sciatic painand/or inflammation by locally administering the clonidine at one ormore target tissue sites (e.g., nerve root, dorsal root ganglion, focalsites of pain, at or near the spinal column, etc.).

In some embodiments, the drug depot can be used to treat one or moretarget tissue sites that are involved in conditions/diseases, such asfor example, rheumatoid arthritis, osteoarthritis, sciatica, carpaltunnel syndrome, lower back pain, lower extremity pain, upper extremitypain, cancer, tissue pain and pain associated with injury or repair ofcervical, thoracic, and/or lumbar vertebrae or intervertebral discs,rotator cuff, articular joint, TMJ, tendons, ligaments, muscles, asurgical wound site or an incision site, postoperative pain or the like.

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., pellet or drug depot) retaining potential for successfulplacement within a mammal. The expression “implantable device” andexpressions of the like import as utilized herein refers to an objectimplantable through surgery, injection, or other suitable means whoseprimary function is achieved either through its physical presence ormechanical properties.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 0.1cm, or preferably within about 10 cm, for example) thereto. For example,the drug dose delivered locally from the drug depot may be, for example,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% lessthan the oral dosage or injectable dose. In turn, systemic side effects,such as for example, liver transaminase elevations, hepatitis, liverfailure, myopathy or constipation may be reduced or eliminated. In someembodiments, the depot is not to be administered at or near the eye.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,or horses.

The term “polydispersity index” or “polydispersity” refers to the ratioof the weight average molecular weight (M_(w)) of the polymer to thenumber-average molecular weight (M_(n)) of the polymer or (M_(w)/M_(n)).

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, and so forth, and combinationsthereof.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, for example,mcg/hr, mcg/day, 10% per day for ten days, etc. As persons of ordinaryskill know, a release rate profile may, but need not, be linear. By wayof a non-limiting example, the drug depot may be a ribbon-like fiberthat releases the drug over a period of time.

The term “solid” is intended to mean a rigid material, while,“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot (e.g., fiber, strip, pellet,etc.) to bend and conform to the surrounding tissue requirements.

“Targeted delivery system” provides delivery of one or more drugs depots(e.g., fibers, strip, pellet, etc.) at or near the target site as neededfor treatment of pain, inflammation or other disease or condition.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide),

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to polyethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “PEA” refers to poly(ester) amides.

The abbreviation “POE” refers to poly(orthoester). The above polymers orcombination of polymers can be in the drug depot (e.g., fiber, strip,pellet, etc.).

Polymeric Material Having Reduced Degradation Time

Polymeric devices are made from polymeric materials which need todegrade over days or years. In the synthesis of biodegradable polymerssuch as homopolymers or copolymers based on lactide (L-lactide,D-lactide, DL-lactide, meso-lactide), glycolide, epsilon-caprolactone,dioxanone, trimethylene carbonate, delta-valerolactone,gamma-butyrolactone the presence of monomers helps in accelerating thedegradation of biodegradable polymers in the body. In many instancesmonomers decompose more rapidly than biodegradable polymers on exposureto moisture. Consequently, the implantation of monomer-containingbiodegradable polymers in medical devices would therefore lead to a moreaccelerated breakdown of the material in the body.

Polymers may have broad molecular weight distributions. For example, thebiodegradable polymers of this application can provide a polymercomposition or blend similar to 100% poly(D,L-lactide) or 100DL SE thathas an inherent viscosity of 0.45-0.55 dL/g, has a molecular weight fromabout 60 kDa and it contains ester end groups. The composition of 100DLSE has a negligible amount of monomeric content which accounts forprolonged polymer degradation time of about 12 months, a desirableproperty for some medical devices. It has been surprisingly discoveredthat by combining biodegradable polymers of a certain moleculardistribution and having increased monomer content, polymeric materialsor blends can be obtained which have a polydispersity index greater than2 and can degrade in less than 6 months, a property desirable forimplantable drug depots useful in treating chronic diseases such assciatica and osteoarthritis.

The breadth of the molecular weight distribution of a polymer can bemeasured by the polydispersity index (M_(w)/M_(n)) of the polymer. Thepolydispersity index or polydispersity is the ratio of theweight-average molecular weight (Mw) of the polymer to thenumber-average molecular weight (M_(n)) of the polymer. Theweight-average molecular weight and the number-average molecular weightof a polymer can be determined by analytical methods, such as gelpermeation chromatography. Similarly, the number-average molecularweight (M_(n)) may be correlated to the intrinsic viscosity:

[η]=(1.019×10−3)·(Mn 0.659), wherein the parameters were also determinedusing gel permeation chromatography. Once the weight-average andnumber-average molecular weights have been determined, thepolydispersity index is easily calculated by dividing the weight-averagemolecular weight by the number average molecular weight, M_(w)/M_(n).More conveniently, however, the molecular weight is determined using astandardized intrincis viscosity assay (ISO 1628-1). The value for theintrinsic viscosity ([η]) thus obtained (expressed in dL/g) may beconverted into the weight average molecular weight (M_(w)) by using thewell-known Mark-Houwink expression.

[η]=K(M_(w))^(α), wherein K and α are specific parameters.

Similarly, the number-average molecular weight (M_(n)) may be correlatedto the intrinsic viscosity:

[η]=(1.019×10−3)(M_(n) 0.659), wherein the parameters were alsodetermined using gel permeation chromatography. A hypotheticallymonodisperse polymer has a polydispersity index of 1.000. Polymers withbroad molecular weight distributions have higher polydispersity indicesand while polymers with narrow molecular weight distributions have lowerpolydispersity indices.

In some embodiments, by increasing the monomer content of thepoly(lactide) polymers, polymer blends are provided having apolydispersity index greater than 1.5 or 1.6 or 1.7 or 1.8 or 1.9 or2.0, 2.1 or 2.2 or 2.3 or 2.4 or 2.5. This allows the desired drugrelease from the medical device (e.g., drug depot) for treatment ofchronic conditions, such as for example, sciatica, osteoarthritis, etc.

As a function of the chemistry of the biodegradable material, themechanism of the degradation process can be hydrolytical or enzymaticalin nature, or both. In various embodiments, the degradation can occureither at the surface (heterogeneous or surface erosion) or uniformlythroughout the drug delivery system depot (homogeneous or bulk erosion).Polymer hydrolysis prompted by reaction with water in tissues is onemechanism which results into degradation of biodegradable polymers. Insome embodiments, some poly(D,L-lactide) polymers have ester end groups(e.g., methyl or ethyl ester end groups), which are hydrophobic and as aresult do not facilitate polymeric degradation by hydrolysis. Otherpoly(D,L-lactide) polymers have carboxylic acid end groups which arehydrophilic which facilitate polymeric degradation by hydrolysis.

Monomer content can be controlled in several ways including theselection of commercial biodegradable polymers with a desirable level ofmonomer concentration. Biodegradable polymers that are useful in thisapplication include 100DL 2E, 100DL, 4A, 100DL 4E, 100DL 4.5A, 100DL4.5E, 100DL 5A, 100DL 5E, 100DL 7E or mixtures thereof, all availablefrom Evonik Industries, Birmingham, Ala., under the trademark RESOMER®100DL 2E is a polymer that has an inherent viscosity of 0.15-0.25 dL/gand a molecular weight of about 7 kDa. It contains 100%poly(D,L-lactide) and has ester end groups. 100DL 4A is a polymer thathas an inherent viscosity of 0.35-0.45 dL/g and a molecular weight ofabout 40 kDa. It contains 100% poly(D,L-lactide) and has carboxylic acidend groups. 100DL 4E is a polymer that has an inherent viscosity of0.35-0.45 dL/g and a molecular weight of about 40 kDa. It contains 100%poly(D,L-lactide) and has ester end groups. 100DL 4.5A is polymer thathas an inherent viscosity of 0.40-0.50 dL/g and a molecular weight ofabout 50 kDa. It contains 100% poly(D,L-lactide) and has carboxylic acidend groups. 100DL 4.5E is polymer that has an inherent viscosity of0.40-0.50 dL/g and a molecular weight of about 50 kDa. It contains 100%poly(D,L-lactide) and has ester end groups. 100DL 5A is polymer that hasan inherent viscosity of 0.45-0.55 dL/g and a molecular weight of about60 kDa. It contains 100% poly(D,L-lactide) and has carboxylic acid endgroups. 100DL 5E is polymer that has an inherent viscosity of 0.45-0.55dL/g and a molecular weight of about 60 kDa. It contains 100%poly(D,L-lactide) and has ester end groups. 100DL 7E is polymer that hasan inherent viscosity of 0.60-0.80 dL/g and has a molecular weight fromabout 80 kDa to about 90 kDa. It contains 100% poiy(D,L-lactide) and hasester end groups.

In some embodiments, monomer content can be increased through additionof monomer to a scaffolding polymer in the extrusion step utilized inthe preparation of the polymeric material. For example, for the polymersof the molecular weight distribution described above, monomer contentcan vary from about 0.01% to about 2.0%. In various embodiments, themonomer content can be 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%,0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%,0.0%9, 0.095%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0,4%5, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%,1.15%, 1,2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%,1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, or 2.0% by weight of the averagemolecular weight of the poly(D,L-lactide) polymer.

In various embodiments, the polymeric material of this applicationcomprises biodegradable polymers having an average molecular weight fromabout 7 kDA to about 80 kDa. In other embodiments, the polymericmaterial comprises biodegradable polymers which have a molecular weightof about 60 kDa.

In some aspects, the polymeric material of this application comprises aplurality of biodegradable polymers forming a polymeric blend having afirst polymer in an amount of about 10%, a second polymer in an amountof about 20%, a third polymer in an amount of about 50% and a fourthpolymer of about 20% by weight. In other aspects, the polymeric blend ofthis application comprises a plurality of biodegradable polymers havinga first polymer in an amount from about 5% to about 15%, a secondpolymer in an amount of about 15% to about 25%, a third polymer in anamount of about 45% to about 55% and a fourth polymer of about 15% toabout 25% by weight.

In some embodiments, the plurality of biodegradable polymers usefill forthe polymeric blends comprises 100DL 2E in an amount of about 10%, 100DL4.5A in an amount of about 20%, 100DL 4.5E in an amount of about 50% and100DL 7E in an amount of about 20% by weight. In other aspects, thepolymeric blend of this application comprises a plurality ofbiodegradable polymers having a first polymer in an amount from about 5%to about 15%, a second polymer in an amount of about 15% to about 25%, athird polymer in an amount of about 45% to about 55% and a fourthpolymer of about 15% to about 25% by weight. These polymer blends can beused to increase or decrease monomer content of the total blend ofpolymers to obtain the desired drug release profile so that the medicaldevice (e.g., drug depot) will degrade during release and be eliminatedby the body over time.

In various aspects, the plurality of biodegradable polymers forming thepolymeric materials or blends of this application comprises one or moremonomers, co-monomers or polymers comprising poly(lactide-co-glycolide)(PLGA), polylactide (PLA), polyglycotide (PGA), D-lactide, D,L-lactide,L-lactide, D,L-lactide co-caprolactone, D,L-lactide-co-ε-caprolactone,L-lactide-co-caprolactone, L-lactide-co-ε-capmlactone,D,L-lactide-co-glycolide-co-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(P-lactide-co-caprolactone), lactide-co-ε-caprolactone),poly(L-lactide-co-ε-caprolactone), poly(D-lactide-co-ε-caprolactone)poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(esteramide) ora combination thereof.

In some embodiments, the polymeric materials or blends of thisapplication can be used to prepare medical devices that require adegradation time of less than 6 months. The polymeric material usefitlfor such medical devices comprises a plurality of polymers having apolydispersity: or molecular weight distribution greater than 1.5 or 1.6or 1.7 or 1.8 or 1.9 or 2.0 or 2.2 or 2.3 or 2.4 or 2.5. In someembodiments, the medical device can be an implantable depot as describedbelow. The implantable depot can be utilized to release a drug or drugsfor treatment of.

Methods for the preparation of polymeric materials or blends having adegradation time of less than 6 months and a polydispersity greater than2 are also provided. In some embodiments, a plurality of biodegradablepolymers comprising a first polymer in an amount of about 10%, a secondpolymer in an amount of about 20%, a third polymer in an amount of about50% and a fourth polymer of about 20% by weight is mixed as a powderblend using mixing techniques such as, for example, granulation,levitation, milling, or the like. In other embodiments, the plurality ofbiodegradable polymers described in this application are mixed and thendissolved in an organic or inorganic solvent, as applicable. Usefulsolvents comprise without limitation n-hexane, cyclohexane, heptanes,methylene chloride, ethyl acetate, acetone or combinations thereof. Inother embodiments the solvents also include polyethylene glycols asesters or ethers, polyethoxylated fatty acids, hydroxylated fatty acids,fatty alcohols, polyethoxylated castor oil, polyethoxylated hydrogenatedcastor oil, polyethoxylated fatty acid from castor oil, polyethoxylatedfatty acid from hydrogenated castor oil, Cremophor, Myrj, Polyoxyl 40stearate, Emerest 2675, Lipal 395, Tween, Span and HCO 50, glycerin,N,N-dimethylacetamide, ethyl alcohol, denatured alcohol, ester, acetone,transcutol or a combination thereof.

In some embodiments an anti-solvent can be added to the polymericmixture or blend to separate the mixture of biodegradable polymers orpolymeric blend having a polydispersity greater than 2 from otherpolymers, co-monomers or monomers. Useful anti-solvents comprise withoutlimitation water, ethanol, methanol, supercritical carbon dioxide,supercritical nitrogen, supercritical water or mixtures thereof.

Clonidine Compounds

When referring to clonidine, unless otherwise specified or apparent fromcontext it is understood that the inventors are also referring topharmaceutically acceptable salts. One well-known commercially availablesalt for clonidine is its hydrochloride salt. Some other examples ofpotentially pharmaceutically acceptable salts include those salt-formingacids and bases that do not substantially increase the toxicity of acompound, such as, salts of alkali metals such as magnesium, potassiumand ammonium, salts of mineral acids such as hydriodic, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, as well as saltsof organic acids such as tartaric, acetic, citric, mane, benzoic,glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.,p-toluenesulfbnic acids, or the like.

Further, when referring to clonidine, the active ingredient may not onlybe in the salt form, but also in the base form (e.g., free base). Invarious embodiments, if it is in the base form, it may be combined withpolymers under conditions in which there is not severe polymerdegradation, as may be seen upon heat or solvent processing that mayoccur with PLGA. or PLA. By way of a non-limiting example, whenformulating clonidine with poly(orthoesters) it may be desirable to usethe clonidine base formulation. By contrast, when formulating clonidinewith PLGA, it may be desirable to use the HCl salt form. In someembodiments, the clonidine may be incorporated into a polymer core witha polymer and then coated with the same or different polymer.

Pharmaceutically acceptable salts of clonidine include salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases, inorganic or organic acids and fatty acids.Salts derived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine,N-ethylpiperidine glucamine, glucosamine, histidine, hydrabamine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethyl amine, tripropylamine, tromethamine, and thelike. When the compound of the current application is basic, salts maybe prepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, rube, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic,pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric,p-toluenesulfonic acid, trifluoroacetic acid, and the like. Fatty acidsalts may also be used, e.g., fatty acid salts having greater than 2carbons, greater than 8 carbons or greater than 16 carbons, such asbutyric, caproic, caprylic, capric, lauric, mystiric, stearic, arachidicor the like.

In some embodiments, in order to reduce the solubility of the clonidineto assist in obtaining a controlled release depot (e.g., fiber, strip,pellet, etc.) effect, clonidine is utilized as the free base or utilizedin a salt which has relatively lower solubility. For example, thepresent application can utilize an insoluble salt such as a fatty acidsalt. Representative fatty acid salts include salts of oleic acid orlinoleic acid. In preferred embodiments fatty acid salts with between 8to 20 carbons are used to produce salts with low solubility, such asclonidine palmeate and clonidine stearate. Most preferably, fatty acidsalts with between 12 to 18 carbons are used. Other embodiments canutilize a lipid soluble salt of clonidine.

In some embodiments, clonidine can be used with a GABA compound in thedrug depot. The GABA compounds used in the treatment methods and in thedevice include compounds of gamma-aminobutyric acid. Such compoundsinclude gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid),pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), vigabatrin(4-aminohex-5-enoic acid), and baclofen(4-amino-3-(4-chlorophenyl)butanoic acid), which are 3′-alkylated GABAcompounds. Additional GABA compounds that may be used are described inSatzinger et U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No.5,563,175; Norwell et al., U.S. Pat. No. 6,020,370; Silverman et al.,U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; WO 02/00209); Silverman etal., PCT Publication No. WO 92/09560; Silverman et al., PCT PublicationNo, WO 93/23383; Horwell et al., PCT Publication No. WO 97/29101,Horwell et al., PCT Publication No. WO 97/33858; Horwell et al, PCTPublication No. WO 97/33859; Bryans et al., PCT Publication No. WO98/17627; Guglietta et al., PCT Publication No. WO 99/08671; Bryans etal., PCT Publication No. WO 99/21824; Bryans et al., PCT Publication No.WO 99/31057; WO 98/23383; Bryans et al., J. Med. Chem, 1998, 41,1838-1.845; Bryans et al., Med. Res. Rev. 1999, 19, 149-177, USGuglietta et al., WO 99/08670; Bryans et al., WO 99/21824; US Bryans etal., UK GB 2 374 595), Belliotti et al., PCT Publication No. WO99/31074; Bryans et al., PCT Publication No. WO 99/31075; Bryans et al.,PCT Publication No. WO 99/61424; Bryans et al., PCT Publication No. WO00/15611; Bryans, PCT Publication No. WO 00/31020; Bryans et al., PCTPublication No. WO 00/50027; and Bryans et al., PCT Publication No. WO02/00209). New classes of GABA compounds, which are bicyclic amino acidderivatives, have been recently described by Bryans et al., PCTPublication No. WO 01/28978; Blakemore et al., PCT Pub. No. WO02/085839; Blakemore et al., U.S. Pat. No. 5,596,900; and Blakemore etal., PCT Pub. No. WO 02/090318. These disclosures are hereinincorporated by reference into the present disclosure.

In one embodiment, the GABA compound comprises1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, baclofen, vigabatrin, gabapentin, pregabalin,gamma-amino-phosphinic acid or1-{[(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid, fengabine, GBL (gamma-Butyrolactone), GHB(gamma-Hydroxybutyric acid, 4-hydroxybutanoic acid or sodium oxybate),picamilon and progabide,(s)-(+)-4-amino-3-(2-methylpropyl)-butanoicacid.

In another embodiment, GABA compounds include pharmaceuticals that canincrease locally the available amount of endogenous GABA or GABA analogsfollowing their local or systemic administration. These includepharmaceuticals that interfere with GABA or GABA analog reuptake such astiagabine, stiripentol, deramciclane, hyperforin or a combinationthereof. GABA compounds also include pharmaceuticals that interfere withthe degradation of GABA or GABA analogs such as phenelzine, gabaculine,valproate, vigabatrin, lemon balm or a combination thereof.

In some embodiments, the GABA compound is released locally from thedevice at a dose of from about 0.3 mg/day or about 1.8 mg/day or about3.6 mg/day to about 180 mg/day or about 360 mg/day. In some embodiments,the GABA compound is released from the device at a dose of 0.75 mg to 16mg per day. In some embodiments, the initial burst or bolus release isabout 2 to 20 times higher from 1 hour to about two weeks than thesustained release daily dose released from the device.

In some embodiments, the GABA compound comprises gabapentin, which isreleased from the device at a dosage of from about 0.3 mg or 1 mg toabout 8 mg, 10 mg, 16 mg or 32 mg per day. In some embodiments, the GABAcompound comprises pregabalin, which is released from the device at adosage of from about 0.1 mg or 0.3mg to about 1 mg, 3 mg, 5 mg or 10 mgper day. In some embodiments, the clonidine can be released from thedepot (e.g., fiber, strip, pellet, etc.) at a dose of 0.002 mg to 16 mgper day.

In some embodiments, the ratio of gabapentin to clonidine would be300:1. For pregabalin, the ratio would he approximately 100:1, in someembodiments, the drug depot releases 300 mg of pregabalin per day.

The GABA compound compliments the anti-inflammatory and analgesic effectof clonidine in the drug depot.

In some embodiments, the drug depot comprises clonidine that is in thedrug depot in an amount of from about 0.1% to about 75% by weight.

In some embodiments, the drug depot comprises both a GABA compound andclonidine in a single formulation. In some embodiments, the GABAcompound can be in a separate depot (e.g., drug depot) from theclonidine.

In some embodiments, a GABA compound, a steroid, bupivacaine, lidocaineand/or clonidine can be administered in an immediate release orsustained release liquid by injection before, after, or during theadministration of the clonidine depot e.g., drug depot).

The clonidine and GABA compound or its pharmaceutically acceptable saltmay be administered with a muscle relaxant. Exemplary muscle relaxantsinclude by way of example and not limitation, alcuronium chloride,atracurium bescylate, carbamate, carbolonium, carisoprodol,chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The drug depot may comprise other therapeutic agents in addition to theclonidine and/or GABA compound as well. These therapeutic agents, invarious embodiments, block the transcription or translation of TNF-α orother proteins in the inflammation cascade. Suitable therapeutic agentsinclude, but are not limited to, integrin antagonists, alpha-4 beta-7integrin antagonists, cell adhesion inhibitors, interferon gammaantagonists, CTLA4-Ig agonists/antagonists (BMS-188667), CD40 ligandantagonists, Humanized anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1mAb (Critical Therapeutics anti-IL2R antibodies (daclizumab,basilicimab), ABX (anti IL-8 antibodies), recombinant human IL-10, orHuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninterleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogs (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), may also be usefulas therapeutic agents for reducing inflammation. It is furthercontemplated that where desirable a pegylated form of the above may beused. Examples of still other therapeutic agents include NF kappa Binhibitors such as glucocorticoids, antioxidants, such asdithiocarbamate, and other compounds, such as, for example,sulfasalazine.

Examples of therapeutic agents suitable for use also include, but arenot limited to an anti-inflammatory agent, an analgesic agent, or anosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine [2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin or tolmetin; as well as antioxidants, such asdithiocarbamate, steroids, such as fluocinolone, cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone, fluticasone or a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor (e.g., GDF-5), a LIM mineralization protein, CDMPor progenitor cells or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, bupivacaine, lidocaine, opioid analgesics such asbuprenorphine, butorphanot, dextromoramide, dezocine,dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,hydrocodone, hydromorphone, ketobemidone, levotnethadyl, mepiridine,methadone, morphine, nalbuphine, opium, oxycodone, papaveretum,pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene,remifentanil, tilidine, tramadoi, codeine, dihydrocodeine, meptazinol,dezocine, eptazocine, flupirtine, amitriptyline, carbamazepine,gabapentin, pregabalin, or a combination thereof.

The therapeutic agent in the drug depot may include, but is not limitedto, members of the fibroblast growth factor family, including acidic andbasic fibroblast growth factor (FGF-1 and FGF-2) and FGF-4, members ofthe platelet-derived growth factor (PDGF) including PDGF-AB, PDGF-BB andPDGF-AA; EGFs; the TGF-β superfamily, including TGF-β1, 2 or 3;osteoid-inducing factor (OIF); angiogenin(s); endothelins; hepatocytegrowth factor or keratinocyte growth factor; members of the bonemorphogenetic proteins (BMP's) BMP-1, BMP-3, BMP-2; OP-1, BMP-2A,BMP-2B, or BMP-7; HBGF-1 or HBGE-2; growth differentiation factors(GDF's); members of the hedgehog family of proteins, including indian,sonic and desert hedgehog; ADMP-1; other members of the interleukin (IL)family; or members of the colony-stimulating factor (CSF) family,including CSF-1, G-CSF, and GM-CSF, or isoforms thereof; or VEGF, NELL-1(neural epidermal growth factor-like 1), CD-RAP (cartilage-derivedretinoic acid-sensitive protein) or combinations thereof.

In some embodiments, the drug depot comprises osteogenic proteins.Exemplary osteogenic proteins include, but are not limited to, OP-1,OP-2, OP-3, BMP-2, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11,BMP-12, BMP-13, BMP-14, BMP-15, GDF-1, GDF-2, GDF-5, GDP-6, GDF-7,GDF-8, GDF-1.0, GDF-11, GDF-12CDMP-1, CDMP-3, DPP, Vg-1, Vgr-1, 60Aprotein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, and TGF-beta. As usedherein, the terms “niorphogen,” “bone morphogen,” “BMP,” “osteogenicprotein” and “osteogenic factor” embrace the class of proteins typifiedby human osteogenic protein 1 (hOP-1).

Exemplary growth factors include, but are not limited to, members of thetransforming growth factor beta family, including bone morphogeneticprotein 2 (BMP-2); bone morphogenetic protein 4 (BMP-4); andtransforming growth factors beta-1, beta-2, and beta-3 (potentkeratinocyte growth factors). Other useful members of the transforminggrowth factor beta family include BMP-3, BMP-5, BMP-6, BMP-9, DPP, Vgl,Ygr, 60A protein, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, CDMP-1, CDMP-2,CDMP-3, BMP-10, BMP-11, BMP-13, BMP-15, Univin, Nodal, Screw, ADMP,Neural, and amino acid sequence variants thereof. Other growth factorsinclude epidermal growth factor (EGF), which induces proliferation ofboth mesodermal and ectodermal cells, particularly keratinocytes andfibroblasts; platelet-derived growth factor (PDGF), which exertsproliferative effects on mesenchymal cells; fibroblast growth factor(FGF), both acidic and basic; and insulin-like growth factor 1 (IGF-1)or 2 (IGF-2), which mediate the response to growth hormone, particularlyin bone growth. Further growth factors include osteogenic proteins. Aparticularly preferred osteogenic protein is OP-1, also known as bonemorphogenetic protein 7 (BMP-7). OP-1 is a member of the transforminggrowth factor beta gene superfamily.

The clonidine may also be administered with non-active ingredients.These non-active ingredients may have multi-functional purposesincluding the carrying, stabilizing and controlling the release of thetherapeutic agent(s). The sustained release process, for example, may beby a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot e.g., fiber, strip,pellet, etc.) will be a solid or semi-solid formulation comprised of abiocompatible material that can be biodegradable.

In some embodiments, the implantable medical device comprises a drugdepot. In various embodiments, a plurality of drug depots (e.g.,pellets) can be administered to a surgical site.

In some embodiments, a plurality of drug depots are provided (e.g., in akit) and administered to a surgical site and triangulate and/or surroundthe site to treat post-operative pain. In various embodiments, aplurality of drug depots comprise about 1, 2, 3, 4, 5, 6, 7, 9 or 10drug depots.

Exemplary excipients, plasticizers, and/or pore forming agents that maybe formulated with clonidine in addition to the biodegradable polymerinclude but are not limited to MgO (e.g., 1 wt. %), MPEG, propyleneglycol, mannitol, trehalose, TBO-Ac, Span-65, Span-85, pluronic F127,sorbitol, cyclodextrin, maltodextrin, pluronic F68, CaCl, dextran,dextran sulphate, dextran phosphate, hydroxypropylcellulose,ethylcellulose, PEG 1500, PEG 400, PEG3350 or combinations thereof. Insome embodiments, the excipients comprise from about 0.001 wt. % toabout 50 wt. % of the formulation. In some embodiments, the excipientscomprise from about 0.001 wt. % to about 40 wt. % of the formulation. Insome embodiments, the excipients comprise from about 0.001 wt. % toabout 30 wt. % of the formulation. In some embodiments, the excipientscomprise from about 0.001 wt. % to about 20 wt. % of the formulation. Insome embodiments, the excipients comprise from about 0.001 wt. % toabout 10 wt. % of the formulation. In some embodiments, the excipientscomprise from about 0.001 wt. % to about 50 wt. % of the formulation. Insome embodiments, the excipients comprise from about 0.001 wt. % toabout 2 wt. % of the formulation.

In some embodiments, the drug depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thetherapeutic agent. However, the pre-determined erosion of the depot(e.g., drug depot) material can also be used to provide for slow releaseof the loaded therapeutic agent(s). Non-biodegradable polymers includebut are not limited to PVC and polyurethane. In some embodiments, aplasticizer is used to lower glass translation temperature in order toaffect stability of the drug depot.

In various embodiments, the drug depot comprises clonidine, bupivacaineor lidocaine and a biodegradable polymer in amorphous, crystalline orsemicrystalline form; where the crystalline form may include polymorphs,solvates or hydrates.

In some embodiments, the clonidine can be in powdered form having aparticle size predominantly in a range from about 3.5 to about 10micrometers that can be reconstituted with the polymer for delivery.

In some embodiments, the drug depot has a modulus of elasticity in therange of about 5×10⁵ dyn/cm². In some embodiments, the drug depot is inthe form of a solid. In some embodiments, the drug depot comprisesclonidine, bupivacaine or lidocaine.

In some embodiments, the clonidine, bupivacaine, lidocaine, and/or GABAcompound is administered in a drug depot that is solid or in semi-solidform. The solid or semi-solid form of the drug depot may have apre-dosed viscosity in the range of about 1 to about 2000 centipoise(cps), 1 to about 200 cps, or 1 to about 100 cps. After the solid orsemi-solid drug depot is administered to the target site, the viscosityof the semi-solid or solid drug depot will increase and the semi-solidwill have a modulus of elasticity in the range of about 1×10² to about6×10⁵ dynes/cm², or 2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about5×10⁵ dynes/cm².

In various embodiments, the semi-solid or solid drug depot may comprisea polymer having a molecular weight, as shown by the inherent viscosity,from about 0.10 dL/g to about 1.2 dL/g or from about 0.20 dL/g to about0.50 dL/g. Other IV ranges include but are not limited to about 0.05 toabout 0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25dL/g, about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g,about 0.30 to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40to about 0.45 dL/g, about 0.45 to about 0.55 dL/g, about 0.50 to about0.70 dL/g, about 0.55 to about 0.6 dL/g, about 0.60 to about 0.80 dL/g,about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g, about 0.90to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 to about 1.3dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5 dL/g, about1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about 1.6 to about1.8 dL/g, about 1.7 to about 1.9 dL/g, or about 1.8 to about 2,1 dL/g.

In some embodiments, the drug depot may comprise an 8% loaded 60:40 LCL5A with a 6.5% content having a 0.4 mm diameter; an 8% loaded 60:40 LCL5A with a 6.6% content having a 0.8 mm diameter; or a 16% loaded 60:40LCL 5A with a 13.2% content having a 0.6 rnm diameter.

In various embodiments, the depot (e.g., fiber, strip, pellet, etc.) maycomprise a bioerodible, a bioabsorbable, and/or a biodegradablebiopolymer that may provide immediate release, or sustained release ofthe clonidine. Examples of suitable sustained release biopolymersinclude but are not limited to poly (alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG),polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids),poly(orthoester)s (POE), poly(esteramide)s, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin Ecompounds, such as alpha tocopheryl acetate, d-alpha tocopherylsuccinate, D,L-lactide, or L-lactide-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isohutyrate) or combinations thereof.

In some embodiments, the drug depot comprises biodegradable polymerscomprising wherein the at least one biodegradable polymer comprises oneor more of poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone, L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide),poly(L-lactide), poly(esteramide) or a combination thereof.

Mannitol, trehalose, dextran, mPEG and/or PEG may be used as aplasticizer for polymer. These plasticizers impart malleability to theresulting formulations. In some embodiments, the polymer and/orplasticizer may also be coated on the drug depot to provide the desiredrelease profile. In some embodiments, the coating thickness may be thin,for example, from about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 micronsto thicker coatings 60, 65, 70, 75, 80, 85, 90, 95, 100 microns to delayrelease of the drug from the depot (e.g., fiber, strip, pellet, etc.).In some embodiments, the range of the coating on the drug depot rangesfrom about 5 microns to about 250 microns or 5 microns to about 200microns to delay release from the drug depot.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caproluctone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide),poly(L-lactide), poly(esteramide) or a combination thereof and has aninherent viscosity of 0.2 to about 0.5 dL/gm or 0.6 to about 1.0 dL/gmand a MW of 30,000 to about 125,000 Da.

In some embodiments, the drug depot comprises one or more polymers(e.g., PLA, PLGA, etc.) having a MW of from about 15,000 to about150,000 Da, from about 25,000 to about 100,000 Da or from about 30,000to about 50,000 Da.

As persons of ordinary skill in the art are aware, in some embodiments,when implantable depot (e.g., fiber, strip, pellet, etc.) compositionshaving a blend of polymers with different end groups are used theresulting formulation will have a lower burst index and a regulatedduration of delivery. For example, one may use polymers with acid (e.g.,carboxylic acid) and ester end groups (e.g., methyl or ethyl ester endgroups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer) there willbe a resulting depot (e.g., fiber, strip, pellet, etc.) compositionhaving a regulated burst index and duration of delivery. For example, adepot (e.g., fiber, strip, pellet, etc.) composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot (e.g., fiber, strip,pellet, etc.) composition having a polymer with a L/G ratio of 65:35 mayhave a duration of delivery of about two months; a depot (e.g., fiber,strip, pellet, etc.) composition having a polymer with a L/G ratio of75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot (e.g., fiber, strip, pellet,etc.) composition having a polymer ratio with a L/G ratio of 85:15 mayhave a duration of delivery of about five months; a depot (e.g., fiber,strip, pellet, etc.) composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot (e.g., fiber, strip, pellet, etc.) compositionhaving a terpolymer of CL/G/L with G greater than 50% and L greater than10% may have a duration of delivery of about one month and a depot(e.g., fiber, strip, pellet, etc.) composition having a terpolymer ofCL/G/L with G less than 50% and L less than 10% may have a durationmonths up to six months. In general, increasing the G content relativeto the CL content shortens the duration of delivery whereas increasingthe CL content relative to the G content lengthens the duration ofdelivery. Thus, among other things, depot (e.g., fiber, strip, pellet,etc.) compositions having a blend of polymers having different molecularweights, end groups and comonomer ratios can be used to create a depot(e.g., fiber, strip, pellet, etc.) formulation having a lower initialburst and a regulated duration of delivery.

The depot (e.g., fiber, strip, pellet, etc.) may optionally containinactive materials such as buffering agents and pH adjusting agents suchas potassium bicarbonate, potassium carbonate, potassium hydroxide,sodium acetate, sodium borate, sodium bicarbonate, sodium carbonate,sodium hydroxide or sodium phosphate; degradation/release modifiers;drug release adjusting agents; emulsifiers; preservatives such asbenzalkonium chloride, chlorobutanol, phenylmercuric acetate andphenylmercuric nitrate, sodium bisulfate, sodium bisulfite, sodiumthiosulfate, thimerosal, methylparaben, polyvinyl alcohol andphenylethyl alcohol; solubility adjusting agents; stabilizers; and/orcohesion modifiers. If the depot (e.g., fiber, strip, pellet, etc.) isto be placed in the spinal area, in various embodiments, the depot(e.g., fiber, strip, pellet, etc.) may comprise sterile preservativefree material.

The depot (e.g., fiber) can be different sizes, shapes andconfigurations. There are several factors that can be taken intoconsideration in determining the size, shape and configuration of thedrug depot. For example, both the size and shape may allow for ease inpositioning the drug depot at the target tissue site that is selected asthe implantation. In addition, the shape and size of the system shouldbe selected so as to minimize or prevent the drug depot from movingafter implantation. In various embodiments, the drug depot can be shapedlike a rod or a flat surface such as a film or sheet (e.g., ribbon-like)or the like. Flexibility may be a consideration so as to facilitateplacement of the drug depot.

In various embodiments, the drug depot can be different sizes, forexample, the drug depot may be a length of from about 0.5 mm to 50 mmand have a diameter of from about 0.01 to about 4 mm. In variousembodiments, as the diameter decreases, the surface area that comes incontact with the bodily fluid of the depot (e.g., fiber, strip, pellet,etc.) increases and therefore release of the drug from the depot (e.g.,fiber, strip, pellet, etc.) increases. In various embodiments, the drugdepot may have a layer thickness of from about 0.005 to 1.0 mm, such as,for example, from 0.05 to 0.75 mm. In various embodiments, the length ofthe drug depot is determined based on the length needed to treat thetarget tissue site.

Radiographic markers can be included on the drug depot to permit theuser to position the depot (e.g., fiber, strip, pellet, etc.) accuratelyinto the target site of the patient. These radiographic markers willalso permit the user to track movement and degradation of the depot(e.g., fiber, strip, pellet, etc.) at the site over time. In thisembodiment, the user may accurately position the depot (e.g., fiber,strip, pellet, etc.) In the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample. X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, calcium phosphate,bismuth, iodine, tantalum, tungsten, and/or metal beads or particles. Invarious embodiments, the radiographic marker could be a spherical shapeor a ring around the depot (e.g., fiber, strip, pellet, etc.).

In some embodiments, a drug depot is provided that controls delivery oftherapeutic agents to local, target tissues and secures itself to atarget tissue site. In some embodiments, the drug depot is a flexible,drug loaded pellet or strip or fiber. In some embodiments, the drugdepot is flexible, biodegradable that is loaded with the drug and/ordrug coated to provide sustained release of a therapeutic to a localtissue site. In some embodiments, drug release is in days to months. Insome embodiments, the drug depot comprises polymers, such as, forexample, 10:90 poly(D,L-lactide-co-caprolactone), 85:15poly(D,L-lactide-co-caprolactone), or 60:40poly(L-lactide-co-caprolactone). Degradation times for the polymerscould be weeks to months. In some embodiments, drugs are used such as,for example, an analgesic, anti-inflammatory and/or steroids, which arecoated on the drug depot or uniformly distributed throughout the drugdepot.

In some embodiments, the drug depot comprises a plurality of pores. Insome embodiments, at least 10% of the pores are between about 10micrometers and about 500 micrometers at their widest points. In someembodiments, at least 20% of the pores are between about 50 micrometersand about 150 micrometers at their widest points. In some embodiments,at least 30% of the pores are between about 30 micrometers and about 70micrometers at their widest points. In some embodiments, at least 50% ofthe pores are between about 10 micrometers and about 500 micrometers attheir widest points. In some embodiments, at least 90% of the pores arebetween about 50 micrometers and about 150 micrometers at their widestpoints. In some embodiments, at least 95% of the pores are between about100 micrometers and about 250 micrometers at their widest points. Insome embodiments, 100% of the pores are between about 10 micrometers andabout 300 micrometers at their widest points.

In some embodiments, the drug depot has a porosity of at least about30%, at least about 50%, at least about 60%, at least about 70%, atleast about 90%. The pore enhances release of the clonidine fortreatment of chronic pain.

In some embodiments, the depot may comprise natural and/or syntheticmaterial. For example, the drug depot may comprise poly(alpha-hydroxyacids), poly (facade-co-glycotide) (PLGA), polylactide polyglycolide(PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids),polyorthoesters (POE), polyaspirins, polyphosphagenes, collagen,hydrolyzed collagen, gelatin, hydrolyzed gelatin, fractions ofhydrolyzed gelatin, elastin, starch, pre-gelatinized starch, hyaluronicacid, chitosan, alginate, albumin, fibrin, vitamin F analogs, such asalpha tocopheryl acetate, d-alpha tocopheryl succinate, polyglycolide(PGA), D-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide),poly(L-lactide), poly(esteramide), dextrans, vinylpyrrolidone, polyvinylalcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive),methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO (pluronics),PEO-PPO-PAA copolymers, PLGA/PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate),polydioxanone, methylmethacrylate (MMA). MMA and N-vinylpyrrolidone,polyamide, oxycellulose, copolymer of glycolic acid and trimethylenecarbonate, polyesteramides, polyetheretherketone,polymethylinethacrylate, silicone, hyaluronic acid, chitosan, orcombinations thereof.

In some embodiments, the depot has a thickness of from 0.25 mm to 5 mm,or from about 0.4 mm to about 2 mm, or 0.4 mm to about 1 mm. In someembodiments, the depot has a length of about 1 mm to about 300 mm orabout 5 mm to 200 mm or about 5 mm to about 150 mm.

In some embodiments, the diameter of the depot can range from 0.1 mm to10 mm. In some embodiments, the diameter of the drug depot can rangefrom 0.1 mm to 5 mm, 0.1 mm to 3 mm or 0.1 mm to 1 mm.

In some embodiments, the depot may be made by injection molding,compression molding, blow molding, thermoforming, die pressing, slipcasting, electrochemical machining, laser cutting, water-jet machining,electrophoretic deposition, powder injection molding, sand casting,shell mold casting, lost tissue scaffold casting, plaster-mold casting,ceramic-mold casting, investment casting, vacuum casting, permanent-moldcasting, slush casting, pressure casting, die casting, centrifugalcasting, squeeze casting, rolling, forging, swaging, extrusion,shearing, spinning, powder metallurgy compaction or combinationsthereof.

In some embodiments, a therapeutic agent (including one or moreclonidine compounds) may be disposed on or in the depot by hand bysoaking, electrospraying, ionization spraying or impregnating, vibratorydispersion (including sonication), nozzle spraying,compressed-air-assisted spraying, brushing and/or pouring.

In some embodiments, the depot may comprise sterile and/or preservativefree material. The depot can be implanted by hand or machine inprocedures such as for example, laparoscopic, arthroscopic,neuroendoscopic, endoscopic, rectoscopic procedures or the like. Insonic embodiments, the initial burst surfaces can be disposed on theedges of the depot so that upon contact with the target tissue site, theedges will begin to release the clonidine. In some embodiments, the bodyof the depot can comprise dense, entangled polymers and have theclonidine to provide slower release of the clonidine.

Alternatively, the clonidine can be disposed homogenously throughout thedepot to provide continuous extended release of the clonidine. In someembodiments, the clonidine can be layered in the depot with someportions having different concentrations to provide burst release andthen slower release of the clonidine in areas that have densecrosslinked polymers, such as for example, in the core of the drugdepot.

The dosage of clonidine released from the depot may be fromapproximately 0.0005 to approximately 960 μg/day. Additional dosages ofclonidine include from approximately 0.0005 to approximately 900 μg/day;approximately 0.0005 to approximately 500 μg/day g/day; approximately0.0005 to approximately 250 μg/day; approximately 0.0005 toapproximately 100 μg/day; approximately 0.0005 to approximately 75μg/day; approximately 0.001 to approximately 70 μg /day; approximately0.001 to approximately 65 mg/day; approximately 0.001 to approximately60 μg/day; approximately 0.001 to approximately 55 mg/day; approximately0.001 to approximately 50 μg/day; approximately 0.001 to approximately45 μg/day; approximately 0.001 to approximately 40 μg/day; approximately0.001 to approximately 35 μg/day; approximately 0.0025 to approximately30 μg/day; approximately 0.0025 to approximately 25 μg/day;approximately 0.0025 to approximately 20 μg/day; approximately 0.0025 toapproximately 15 μg/day; approximately 0.0025 to approximately 10μg/day; approximately 0.0025 to approximately 5 μg/day; andapproximately 0.0025 to approximately 2.5 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 10 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 5.mu.g μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to 2.5 μg/day. In some embodiments, the amount ofclonidine is between 40 and 600 μg/day. In some embodiments, the amountof clonidine is between 200 and 400 μg/day.

In some embodiments, the therapeutically effective dosage amount (e.g.,clonidine dose) and the release rate profile are sufficient to reduceinflammation and/or pain for a period of at least 14 days, for example,14-90 days, 14-30 days, 14-60 days, 21-90 days, 21-180 days; 14-210days, or 14 days to 6 months or less than 6 months or 1 year or longer.

In some embodiments, the clonidine depot is designed for a bolus dose orburst dose within 1, 2, or 3 days after implantation to provide animmediate release of the clonidine for treatment of pain and/orinflammation.

In some embodiments, the depot has a modulus of elasticity in the rangeof about 1×10² to about 6×10⁵ dynes/cm², or 2×10⁴ to about 5×10⁵dynes/cm², or 5×10⁴ dynes/cm² to about 5×10⁵ dynes/cm².

In some embodiments, the semi-solid or solid depot 10 may comprise apolymer having a molecular weight, as shown by the inherent viscosity,from about 0.10 dL/g to about 1.2 dL/g or from about 0.10 dL/g to about0.40 dL/g. Other IV ranges include but are not limited to about 0.05 toabout 0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25dL/g, about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g,about 0.30 to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40to about 0.45 dL/g, about 0.45 to about 0.55 dL/g, about 0.50 to about0.70 dL/g, about 0.55 to about 0.6 dL/g, about 0.60 to about 0.80 dL/g,about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g, about 0.90to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 to about 1.3dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5 dL/g, about1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about 1.6 to about1.8 dL/g, about 1.7 to about 1.9 dL/g, or about 1.8 to about 2.1 dL/g,or about 1.9 to about 2.5 dL/g.

In some embodiments, the drug depot may have a burst release surfacethat releases about 10%, 15%, 20%, 75%, 10%, 35%, 45%, to about 50% ofthe clonidine over 24 or 48 hours,

In some embodiments, the depot comprises a polymer having an averagemolecular weight of the polymer can be from about 1000 to about10,000,000 or about 1,000 to about 1,000,000 Da; or about 5,000 Da toabout 500,000 Da; or about 10,000 Da to about 100,000 Da; or about20,000 Da to 50,000 Da or about 60,000Da to about 80,000Da.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In some embodiments, the depot may comprise a viscosity enhancing agentsuch as, for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcelluloseand salts thereof, Carbopol, poly-(hydroxyethyl-methacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethy methacrylate),polymethyl-methacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In some embodiments, the depot may comprise gelatin, collagen, silk,elastin, fibrin and polysaccharide-derived polymers like agarose, andchitosan, glucomannan gel, hyaluronic acid, polysaccharides, such ascross-linked carboxyl-containing polysaccharides, or a combinationthereof. In some embodiments, the drug depot may comprise polyvinylalcohol, acrylamides such as polyactylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(e.g., PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the depot, microspheres may be dispersed within the depot,the microspheres being loaded with clonidine. In one embodiment, themicrospheres provide for a sustained release of the clonidine.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse theclonidine. In some situations, this may be desirable; in others, it maybe more desirable to keep the clonidine tightly constrained to awell-defined target site. The present disclosure also contemplates theuse of adherent gel or adhesive to constrain the depot close to thetarget tissue site. In this embodiment, an adherent gel or adhesive isused to anchor the depot to the target tissue site. The adherent gel oradhesive can, like the depot, also have the therapeutic agent disposedwithin it. In this way, the depot and the adhesive release thetherapeutic agent (e.g., clonidine, statin, etc.) at or near the targettissue site.

Drug Depot Delivery

It will be appreciated by those with skill in the art that the depot(e.g., fiber, pellet, etc.) can be administered to the target site usinga “cannula” or “needle” that can be a part of a drug delivery devicee.g., a syringe, a gun drug delivery device, or any medical devicesuitable for the application of a drug to a targeted organ or anatomicregion. The cannula or needle of the device is designed to cause minimalphysical and psychological trauma to the patient.

In some embodiments, the depot can be sutured to a target tissue siteusing a suturing needle. The dimensions of the needle, among otherthings, will depend on the site for implantation. For example, the widthof the muscle planes in different surgical procedures can vary from 1-40cm. Thus, the needle, in various embodiments, can be designed for thesespecific areas.

Needles may have different shapes such as for example half curved or skishaped, ¼ circle, ⅜ circle, ½ circle, ⅝ circle, compound curve or thelike. The thickness of the needle will also depend on the site ofimplantation. In various embodiments, the thickness includes, but is notlimited to, from about 0.05 to about 1.655. The gauge of the needle maybe the widest or smallest diameter or a diameter in between forinsertion into a human or animal body. The widest diameter is typicallyabout 14 gauge, while the smallest diameter is about 25 gauge. Invarious embodiments the gauge of the needle or cannula is about 18 toabout 22 gauge.

In various embodiments, like the drug depot, the cannula or needleincludes dose radiographic markers that indicate location at or near thesite beneath the skin, so that the user may accurately position thedepot (e.g., fiber) at or near the site using any of the numerousdiagnostic imaging procedures. Such diagnostic imaging proceduresinclude, for example, X-ray imaging or fluoroscopy. Examples of suchradiographic markers include, but are not limited to, barium, bismuth,tantalum, tungsten, iodine, calcium, and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot may be steritizable. In various embodiments, one or morecomponents of the drug depot are sterilized by radiation in a terminalsterilization step in the final packaging. Terminal sterilization of aproduct provides greater assurance of sterility than from processes suchas an aseptic process, which require individual product components to besterilized separately and the final package assembled in a sterileenvironment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity, E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot (e.g., fiber)and/or one or more components of the device, including, but not limitedto, gas sterilization, such as, for example, with ethylene oxide orsteam sterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot combined together to be used to implantthe drug depot. The kit may include the drug depot device in a firstcompartment. The second compartment may include a canister holding thedrug depot and any other instruments needed for the localized drugdelivery. A third compartment may include gloves, drapes, wounddressings and other procedural supplies for maintaining sterility of theimplanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may include an agent for radiographic imaging. Each tool maybe separately packaged in a plastic pouch that is radiation sterilized.A cover of the kit may include illustrations of the implanting procedureand a clear plastic cover may be placed over the compartments tomaintain sterility. In some embodiments, a kit is provided withinstruction to use an injectable drug from another kit.

In various embodiments, a method for delivering a therapeutic agent intoa site of a patient is provided, the method comprising inserting aneedle at or near a target tissue site and suturing the drug depot atthe target site beneath the skin of the patient. In this way unwantedmigration of the drug depot away from the target site is reduced oreliminated.

In some embodiments, the drug depot can be delivered to any site beneaththe skin, including, but not limited to, at least one muscle, ligament,tendon, cartilage, spinal disc, spinal ibraminal space, near the spinalnerve root, connective tissue, fascia, subcutaneous space, or spinalcanal.

In some embodiments, it is preferable to co-administer clonidine with anantagonist to counteract undesirable effects, for example the bloodpressure decrease that can be caused by clonidine. Exemplary antagonistsinclude but are not limited to phentolamine, yohimbine, tolazoline andpiperoxane. Additionally, compounds such as 5-fluorodeoxyuridine (FUDR)and 3,4 dehydroprolene may also be included. These compounds may preventor reduce glial and fibroblastic scar formation associated with sometypes of surgeries.

Another embodiment is directed to a method for treating a mammalsuffering from pain, said method comprising administering atherapeutically effective amount of clonidine at a target site beneaththe skin. The clonidine (or pharmaceutically acceptable salt) may forexample be administered locally to the target tissue site disposedwithin or on a drug depot.

In some embodiments, the clonidine is encapsulated in a plurality ofmatrices comprising microparticles, microspheres, microcapsules, and/ormicrofibers and then put into a drug depot.

In some embodiments there is a method for making an implantable drugdepot. The method may comprise combining a biocompatible polymer and atherapeutically effective amount of clonidine or a pharmaceuticallyacceptable salt thereof and forming the implantable drug depot from thecombination.

Method of Making the Depot

In various embodiments, the drug depot comprising the clonidine can bemade by combining a biocompatible polymer and a therapeuticallyeffective amount of elonidine or pharmaceutically acceptable saltthereof and forming the implantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot (e.g., fiber, pellet, strip, etc.) to obtain the desired releaserate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: clonidine and other therapeuticagent(s) and other optional additives such as radiographic agent(s),etc. In dissolved or dispersed form. This results in a polymeric drugdepot region containing these species after solvent removal. In otherembodiments, a solution containing solvent with dissolved or dispersedtherapeutic agent is applied to a pre-existing polymeric region, whichcan be formed using a variety of techniques including solutionprocessing and thermoplastic processing techniques, whereupon thetherapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot (e.g., fiber,pellet, strip, etc.) or portions thereof include molding techniques (forexample, injection molding, rotational molding, and so forth), extrusiontechniques (for example, extrusion, co-extrusion, multi-layer extrusion,and so forth) and casting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: clonidine,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, clonidine may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, Banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the clonidine containing drug depot. Conversely,in another embodiment, the biocompatible polymer can be precompoundedwith the therapeutic agent under conditions of reduced temperature andmechanical shear. This precompounded material is then mixed with, forexample, a radio-opacifying agent, also under conditions of reducedtemperature and mechanical shear, and the resulting mixture is shapedinto the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depot(e.g., fiber) is formed comprising PLGA or PLA polymer, aradio-opacifying agent (e.g., bismuth subcarbonate), and a therapeuticagent prone to degradation by heat and/or mechanical shear (e.g.,clonidine), in various embodiments, the PGLA or PLA can be premixed withthe radio-opacifying agent at temperatures of about, for example, 150°C. to 170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can he mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min.). It is noted that this processing temperature iswell below the melting points of clonidine because processing at orabove these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot (e.g., fiber, Pellet, strip, etc.) isshaped into the desired form, also under conditions of reducedtemperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric drug depot layers or regions that havepermeability to fluids to allow immediate and/or sustained drugrelease). Multi-region depots (e.g., fibers, pellet, strip, etc.) canalso be formed by other processing and shaping techniques such asco-injection or sequential injection molding technology.

In various embodiments, the depot (e.g., fiber, pellet, strip, etc.)that may emerge from the thermoplastic processing (e.g., pellet) iscooled. Examples of cooling processes include air cooling and/orimmersion in a cooling bath. In some embodiments, a water bath is usedto cool the extruded depot (e.g., fiber, pellet, strip, etc.). However,where a water-soluble therapeutic agent such as clonidine is used, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot (e.g., fiber) surface, thuscontrolling or minimizing a high drug dose “initial burst” or “bolusdose” upon implantation or insertion if this is release profile is notdesired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot (e.g.,fiber) to the desired shape. In various embodiments, clonidine is usedand mixed or sprayed with the PLGA or PEG550 polymer, and the resultingdepot (e.g., fiber) may be formed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: clonidine, wherein the clonidine comprises from about 0.1wt. % to about 40 wt. % of the formulation, and at least onebiodegradable polymer. in some embodiments, the clonidine comprises fromabout 3 wt. % to about 20 wt. %, about 3 wt. % to about 18 wt. %, about5 wt. % to about 15 wt. %, 0.1 wt % to about 10 wt %, about 0.1 wt % toabout 3 wt %, or about 7.5 wt. % to about 12.5 wt. % of the formulation.By way of example, when using a 5% -15% clonidine composition, the moleratio of clonidine to polymer would be from approximately 16-53 whenusing an approximately 80 kDalton polymer that has a 267 grams/moleratio. By way of another example, when using a 5%-15% clonidine base inthe composition, the mole ratio of clonidine base to polymer would befrom approximately 18-61 with a mole mass of 230 g/triol.

In some embodiments, the clonidine can be in the formulation in anamount of about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 15%, or 40% by weightbased on the total weight of the formulation.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90% 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on the total weight of the depot (e.g.,fiber) and the remainder is active and/or inactive pharmaceuticalingredients.

In some embodiments, the at least one biodegradable polymer comprisespoly(laetic-co-glycolide) (PLGA) or poly(orthoester) (POE) or acombination thereof. The polylactic-co-glycolide) may comprise a mixtureof polyglycolide. (PGA) and polylactide and in some embodiments, in themixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactide:and 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size (e.g., clonidine) is fromabout o 30 micrometers, or about 2 microns to about 20 microns, or from30 microns to 100 microns, however, in various embodiments ranges fromabout it micron to 250 microns may be used. In some embodiments, thebiodegradable polymer comprises at least 50 wt. %, at least 60 wt. %, atleast 70 wt. %, at least 80 wt. % of the formulation, at least 85 wt. %of the formulation, at least 90 wt. % of the formulation, at least 95wt. % of the formulation or at least 97 wt. % of the formulation. Insome embodiments, the at least one biodegradable polymer and theclonidine are the only components of the pharmaceutical formulation.

In sonic embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers. In some embodiments, at least 80%of the particles have a size from 5 microns to about 100 microns on avolume basis.

In some embodiments, at least 75% of the particles have a size fromabout 0.5 micrometer to about 100 micrometers. In some embodiments, atleast 85% of the particles have a size from about 0.5 micrometers toabout 100 micrometers. In some embodiments, at least 95% of theparticles have a size from about 0.5 micrometer to about 100micrometers. In some embodiments, all of the particles have a size fromabout 0.5 micrometer to about 100 micrometers. In some embodiments, atleast 80% of the particles have a size from 2 microns to about 50microns on a volume basis.

In some embodiments, there is a pharmaceutical formulation comprising:clonidine, wherein the clonidine is in the form of a hydrochloride salt,and comprises from about 0.1 wt. % to about 30 wt. % of the formulation,and at least one biodegradable polymer, wherein the at least onebiodegradable polymer comprises poly(lactide-co-glycolide) (orpoly(lactic-co-glycolic acid)) or poly(orthoester) or a combinationthereof, and said at least one biodegradable polymer comprises at least70 wt. % of said formulation.

In some embodiments, the drug depot comprises about 95 wt %poiy(D,L-lactide) and 5 wt % clonidine HCl where the polymer has anester end group and 50,000-70,000 Da MW and an IV 0.45-0.55 dL/g and hasa burst release of under 10% of the amount of drug in the depot (e.g.,fiber, pellet, strip, etc.) within 24 hours (e.g., 5-10 wt %) or 2-40mcg in 24 hours. This formulation has 50% of total cumulative doseremaining for at least 60 days. About 80% of the particles in this depot(e.g., fiber) including the clonidine are from about 5 to about 150microns or 5-100 microns. The depot (e.g., fiber) releases about 0.5mcg/day up to about 5 mcg/day of clonidine in 24 hours and thencontinues release for 70 days,

In some embodiments, the drug depot comprises about 92 wt %poly(D,L-lactide) and 8 wt % clonidine HCl where the polymer has anester end group and the polymer comprises 50,000-70,000 Da MW and an IVof about 0.45-0.55 dL/g and has a burst release of under 10% of theamount of drug in the depot (e.g., fiber) within 24 hours (e.g., 5-10%)or 5-6 mcg in 24 hours and then 1 to 20 mcg/day with a constant releasefor about 50 days, and then about 0.1 mcg to about 10 mcg/day for 70days. This formulation has 50% of total cumulative dose remaining for atleast 30-42 days and less than 80% cumulative drug release by 70 days.About 80% of the particles in this depot (e.g., fiber) including theclonidine are from about 5 to about 150 microns or 5-100 microns.

In some embodiments, the drug depot comprises about 85 wt %poly(D,L-lactide) and 15 wt % clonidine HCl where the polymer has anester end group and the polymer comprises 50,000-70,000 Da MW and an IVof about 0.45-0.55 dL/g and has a burst release of under 10% of theamount of drug in the depot (e.g., fiber) within 24 hours (e.g., 5-10%)or 20-150 mcg in 24 hours and then 5 to 80 mcg/day with a constantrelease for about 30 days, and then about 0.1 mcg to about 5 mcg/day for70 days. This formulation has about 80% of total cumulative dosereleased within 35 days and 20% over several months. About 80% of theparticles in this depot (e.g., fiber) including the clonidine are fromabout 5 to about 150 microns or 5-100 microns.

In some embodiments, there is a pharmaceutical formulation comprisingclonidine, wherein the clonidine is in a mixture of clonidinehydrochloride and clonidine base and the mixture comprises from about0.1 wt. % to about 30 wt. % of the formulation and a polymer comprisesat least 70% of the formulation. In some embodiments, the polymer inthis formulation is polyorthoester.

In some embodiments, the formulation comprises a drug depot thatcomprises a biodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolyticat orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(e.g., fiber) (homogeneous or bulk erosion). Polyorthoester can beobtained from A.P. Pharma, Inc. (Redwood City, Calif.) or through thereaction of a bis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there are methods for treating acute pain. Thesemethods comprise: administering a pharmaceutical composition to anorganism, wherein said pharmaceutical composition (e.g., clonidine)comprises from about 0.1 wt. % to about 30 wt. % of the formulation, andat least one biodegradable polymer. In some embodiments, the loading isfrom about 0.1 wt % to about 10 wt %, about 0.1 wt % to about 3 wt %, 1wt % to about 25 wt %, or about 5 wt. % to about 10 wt. %. In someembodiments, the loading is from about 10 wt. % to about 70 wt. %.

In some embodiment there is a higher loading of clonidine, e,g., atleast 20 wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %,at least 60 wt. %, at least 70 wt.%, at least 80 wt. %, or at least 90wt. %.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)drug depots comprising the pharmaceutical formulations may be placedaround the target tissue site (also known as the pain generator or paingeneration site) such that the target tissue site falls within a regionthat is either between the formulations when there are two, or within anarea whose perimeter is defined by a set of plurality of formulations.

In some embodiments, when the drug depot is in pellet form and comprises5%, 8% or 15% clonidine HCL to provide pain relief for chronicconditions (e.g., sciatica) for more than 30 days, one drug depot maynot be enough. Therefore, in this embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 pellets may be used to provide sufficient pain relief. These 1-10drug depots/pellets can be triangulated around the pain generator toprovide pain relief.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.50 mm and a length of 4 mm. It should be noted thatparticle size may be altered by techniques such as mora and pestle,jet-drying or jet milling.

In some embodiments, clonidine is released at a rate of 2-3 μg per dayfor a period of at least three days. In some embodiments, this releaserate continues for, at least ten days, at least fifteen days, at leasttwenty-five days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days. Forsome embodiments, 300-425 micrograms of clonidine as formulated with abiopolymer are implanted into a person at or near a target tissue site,if clonidine is implanted at multiple sites that triangulate the targetsite then in some embodiments, the total amount of clonidine at eachsite is a fraction of the total 300-425 micrograms. For example, one mayimplant a single dose of 324 micrograms at one site, or two separatedoses of 162 micrograms at two sites, or three separate dose of 108micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal dose that might have been administered in a single application, itis important to remember that each site will independent have a releaseprofile, and the biopolymers' concentration and substance should beadjusted accordingly to ensure that the sustain release occurs oversufficient time.

In some embodiments, clonidine is released at a rate of 7-20 μg per dayfor a period of at least three days. In some embodiments, this releaserate continues for, at least ten days, at least fifteen days, at leasttwenty-five days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days. Forsome embodiments, 900-1050 micrograms of clonidine as formulated with abiopolymer are implanted into a person at or near a target tissue site.If clonidine is implanted at multiple sites that triangulate the targetsite then in some embodiments, the total amount of clonidine at eachsite is a fraction of the total 900-1050 micrograms. For example, onemay implant a single dose of 975 micrograms at one site, or two separatedoses of 650 micrograms at two sites, or three separate dose of 325micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal dose that might have been administered in a single application, itis important to remember that each site will independent have a releaseprofile, and the biopolymers' concentration and substance should beadjusted accordingly to ensure that the sustain release occurs oversufficient time.

The dosage of clonidine may be from approximately 0.0005 toapproximately 960 μg/day. Additional dosages of clonidine include fromapproximately 0.0005 to approximately 900 μg/day; approximately 0.0005to approximately 500 μg/day; approximately 0.0005 to approximately 250μg/day; approximately 0.0005 to approximately 100 μg/day, approximately0.0005 to approximately 75 μg/day; approximately 0.001 to approximately70 μg/day; approximately 0.001 to approximately 65 μg/day, approximately0.001 to approximately 60 μg/day; approximately 0.001 to approximately55 μg/day; approximately 0.001 to approximately 50 μg/day; approximately0.001 to approximately 45 μg/day; approximately 0.001 to approximately40 μg/day; approximately 0.001 to approximately 35 μg/day; approximately0.0025 to approximately 30 μg/day; approximately 0.0025 to approximately25 μg/day; approximately 0.0025 to approximately 20 μg/day;approximately 0.0025 to approximately 15 μg/day; approximately 0.0025 toapproximately 10 μg/day; approximately 0.0025 to approximately 5 μg/day;and approximately 0.0025 to approximately 2.5 μg/day. In anotherembodiment, the dosage of clonidine is from approximately 0.005 toapproximately 15 μg/day. In another embodiment, the dosage of clonidineis from approximately 0.005 to approximately 10 μg/day. In anotherembodiment, the dosage of clonidine is from approximately 0.005 toapproximately 5 μg/day. In another embodiment, the dosage of clonidineis from approximately 0.005 to 2.5 μg/day. In some embodiments, theamount of clonidine is between 40 and 600 μg/day. In some embodiments,the amount of clonidine is between 200 and 400 μg/day.

In some embodiments, the therapeutically effective dosage amount (e.g.,clonidine dose) and the release rate profile are sufficient to reduceinflammation and/or pain for a period of at least one day, for example,1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12. days; 3-14 days; 7-10days, 7-14 days, 7-21 days, 7-30 days, 7-50 days; 7-90 days, 7-140 days,14-140 days, 3 days to 135 days, 3 days to 180 days, or 3 days to 6months or 1 year or longer.

In some embodiments the clonidine in the drug depot is designed for abolus dose or burst dose within 1, 2, or 3 days after implantation toprovide an immediate release of the clonidine for treatment of painand/or inflammation.

In some embodiments, the clonidine drug depot is administeredparenterally, e.g., by injection. In some embodiments, the injection isintrathecal, which refers to an injection into the spinal canal(intrathecal space surrounding the spinal cord). An injection may alsobe into a muscle or other tissue. In other embodiments, the clonidinedepot (e.g., fiber) is administered by placement into an open patientcavity during surgery.

In some embodiments, the drug depot (i) comprises one or more immediaterelease layer(s) that is capable of releasing about 5% to about 20% ofthe clonidine or pharmaceutically acceptable salts thereof relative to atotal amount of the clonidine or pharmaceutically acceptable saltthereof loaded in the drug depot (e.g., fiber) over a first period of upto 48 hours and (ii) one or more sustain release layer(s) that iscapable of releasing about 21% to about 99% of the clonidine orpharmaceutically acceptable salt thereof relative to a total amount ofthe clonidine or pharmaceutically acceptable salt thereof loaded in thedrug depot (e.g., fiber) over a subsequent period of up to 3 days to 90days, 150 days, 180 days, or 6 months to 1 year.

In some embodiments, there is a drug depot (e.g., fiber) comprisingclonidine or clonidine hydrochloride and a polymer, wherein the polymeris one more of various embodiments, the drug depot (e.g., fiber)comprises poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof.

In some embodiments, the polymer drug depot of the present applicationenables one to provide efficacy of the active ingredient that isequivalent to subcutaneous injections that deliver more than 2.5 timesas much drug.

In some embodiments, the drug depot comprises a polymer having 65 mol. %poly L-lactide and 35 mol. % caprolactone, where the poly(L-lactide-co-caprolactone) has a MW of 30,000 to 40,000 Da and an IV ofabout 0.5-0.6 dL/g and has a burst release of under 35% of the amount ofdrug in the depot (e.g., fiber) within 24 hours (e.g., 5-15% within 4hours). The drug depot comprises clonidine in an amount of 3-8 wt. %.The drug depot releases 400 mcg to about 1000 mcg for 7 days, which isabout 40 mcg/day. This drug depot contains 5-10 wt % mannitol as anexcipient. The clonidine has a particle size of 25 microns or less and a90% volume diameter less than 50 microns. The degradation time in thebody is not more than 8 months and the drug depot releases all of theclonidine within 2-4 weeks.

In some embodiments, the drug depot comprises a polymer having 10 mol. %poly D-L-lactide and 90 mol. % caprolactone, where the poly(D,L-lactide-co-caprolactone) has a MW of 50,000 to 125,000 Da and an IVof about 0.6 dL/g and has a burst release of under 25% of the amount ofdrug in the drug depot within 24 hours (e.g., 5-15% within 4 hours). Thedrug depot comprises clonidine in an amount of 3-10 wt. %. The drugdepot releases 400 mcg to about 1000 mcg for 7 days, which is about 40mcg/day. This drug depot contains from about 1% to about 5% by weight ofmannitol or trehalose as a pore forming agent or plasticizer. Theclonidine has a particle size of 5 microns or less and a 90% volumediameter less than 20 microns. The degradation time in the body is notmore than 12 months and the drug depot (e.g., fiber) releases all of theclonidine within 2-4 weeks. As you drop the drug load the drug releasedfrom the depot (e.g., fiber) is faster.

EXAMPLES

The examples below with respect to certain formulations comprisingbiodegradable polymeric blends of this application show particularlyadvantageous results.

In this application several polymeric materials having a polydispersitygreater than 2 are prepared by mixing polylactide polymers of havingdifferent molecular weight distributions and different intrinsicviscosities.

The codes for the polymers are explained as follows. The first number ornumbers refer to monomer mole percentage ratio of DL-lactide (e.g.,polylactide) to glycolide (e.g., poly-glycolide). The letter code thatfollows the first number refers to the polymer(s) and is the polymeridentifier. The second number, which follows the letter code for thepolymer, is the target IV designator and is 10 times the midpoint of arange in dL/g. The meanings of certain IV designators are reflected inTable A.

The inherent viscosity (IV) designations for the polymers are mentionedin Table A below. In some embodiments, the polymers can have thefollowing inherent viscosities.

TABLE A IV Target Designator IV Range dL/g 1 0.05 - 0.15 1.5 0.10 - 0.202 0.15 - 0.25 2.5 0.20 - 0.30 3 0.25 - 0.35 3.5 0.30 - 0.40 4 0.35 -0.45 4.5 0.40 - 0.50 5 0.45 - 0.55 6 0.50 - 0.70 7 0.60 - 0.80 8 0.70 -0.90 9 0.80 - 1.0  10 1.0 - 1.2

The final letter within the code of the polymer is the end groupdesignator. For examples “E” refers to an ester end group, while “A”refers to an acid end group.

Biodegradable polymers that are useful in these examples are describedbelow. 100DL 2E is a polymer that has an inherent viscosity of 0.15-0.25dL/g and a molecular weight of about 7 kDa. It contains 100%poly(D,L-lactide) that has ester end groups and is available from EvonikIndustries, Birmingham, Ala., under the trademark RESOMER®. 100DL 4.5Ais polymer that has an inherent viscosity of 0.40-0.50 dL/g and amolecular weight of about 50 kDa. It contains 100% poly(D,L-lactide)that has carboxylic acid end groups and is available from Evonikindustries, Birmingham, Ala., under the trademark RESOMER®. 100DL 4.5Eis polymer that has an inherent viscosity of 0.40-0.50 dL/g and amolecular weight of about 50 kDa. It contains 100% poly(D,L-lactide)that has ester end groups and is available from Evonik industries,Birmingham. Ala., under the trademark RESOMER®. 100DL 7E is polymer thathas an inherent viscosity of 0.60-0.80 dL/g and has a molecular weightfrom about 80 kDa to about 90 kDa. It contains 100% poly(D,L-lactide)that has ester end groups and is available from Evonik Industries,Birmingham, Ala., under the trademark RESOMER®.

Example 1

In this example, upon mixing 10% by wt. 100DL 2E with 20% by wt. 100DL4.5A, 50% by wt. 100DL 4.5E and 20% by wt. 100DL WE a polymer blendwould be obtained having a polydispersity greater than 2 that results ina polymer degradation time of less than 6 months.

Example 2

This example illustrates another polymer blend which can be obtained bymixing 5% by wt. 100DL 2E with 25% by wt. 100DL 4.5A, 50% by wt. 100DL4.5E and 20% by wt. 100DL 7E a polymer blend obtains having apolydispersity greater than 2 that will result in a polymer degradationtime of less than 6 months.

Example 3

This example illustrates another polymer blend which can be obtained bymixing 5% by wt. 100DL 2E with 25% by wt. 100DL 4.5A, 55% by wt. 100DL4.5E and 25% by wt. 100DL 7E a polymer blend obtains having apolydispersity greater than 2 that will result in a polymer degradationtime of less than 6 months.

Example 4

This example describes another polymer blend which can be obtained bymixing 10% by wt. 100DL 2E with 20% by wt. 100DL 4.5A, 55% by wt. 100DL4,5E and 15% by wt. 100DL 7E a polymer blend obtains having apolydispersity greater than 2 that will result in a polymer degradationtime of less than 6 months.

Example 5

This example describes yet another polymer blend which can be obtainedby mixing 10% by wt. 100DL 2E with 15% by wt. 100DL 4.5A, 50% by wt.100DL 4.5E and 25% by wt. 100DL 7E a polymer blend obtains having apolydispersity greater than 2 that results in a polymer degradation timeof less than 6 months.

Example 6

In this example, another polymer blend can be obtained by mixing 10% bywt. 100DL 2E with 20% by wt. 100DL 4.5A, 55% by wt. 100DL 4.5E and 15%by wt. 100DL 7E a polymer blend obtains having a polydispersity greaterthan 2 that results in a polymer degradation time of less than 6 months.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A polymeric material comprising a plurality ofbiodegradable polymers having a polydispersity or molecular weightdistribution from about 1.5 to about 2.5.
 2. A polymeric material ofclaim 1, wherein the plurality of biodegradable polymers have apolydispersity (M_(w)/M_(n)) of greater than
 2. 3. A polymeric materialof claim 1, wherein (i) the plurality of biodegradable polymers have amolecular weight from about 50 kDA to about 70 kDa; or (ii) theplurality of biodegradable polymers have a molecular weight of about 60kDa.
 4. A polymeric material of claim 1, wherein (i) the plurality ofbiodegradable polymers comprises a first polymer in an amount from about5% to about 15%, a second polymer in an amount from about 15% to about25%, a third polymer in an amount from about 45% to about 55% oroptionally a fourth polymer in an amount from about 15% to about 25% byweight; or (ii) the plurality of biodegradable polymers comprises afirst polymer in an amount of about 10%, a second polymer in an amountof about 20%, a third polymer in an amount of about 50% and a fourthpolymer in an amount of about 20% by weight.
 5. A polymeric material ofclaim 4, wherein the first polymer comprises 100% poly(D,L- lactide)having ester end groups, the second polymer comprises 100%poly(D,L-lactide) having carboxylic acid end groups, the third polymercomprises 100% poly(D,L-lactide) having ester groups and the fourth polycomprises 100% poly(D,L-lactide) having ester groups.
 6. A polymericmaterial of claim 5, wherein the first polymer has an inherent viscosityfrom about from about 0.15 to about 0.25 dL/g, the second polymer has aninherent viscosity from about 0.40 to about 0.50 dL/g, the third polymerhas an inherent viscosity from about 0.40 to about dL/g and the fourthpolymer has an inherent viscosity from about 0.60 to about 0.80dL/g. 7.A polymeric material of claim 1, wherein the plurality of biodegradablepolymers comprises one or more monomers, co-monomers or polymerscomprising poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, L-lactide, D,L-lactide co-caprolactone,L-lactide-co-caprolactone, D,L-lactide-co-glycolide-co-caprolactone,poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone),poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide),poly(L-lactide), poly(esteramide) or a combination thereof.
 8. A medicaldevice comprising a plurality of biodegradable polymers having apolydispersity or molecular weight distribution from about 1.5 to about2.5.
 9. A medical device according to claim 8, wherein the biodegradablepolymers have a polydispersity or molecular weight distribution greaterthan 1.8, 1.9, 2.0, 2.1, 2.2, 2.4 or 2.5.
 10. A medical device of claim8, wherein the implantable depot further comprises an activepharmaceutical ingredient.
 11. A medical device of claim 10, wherein theactive pharmaceutical ingredient is present in an amount from about 0.1%to about 20% by weight of the medical device.
 12. A medical device ofclaim 11, wherein the active pharmaceutical ingredient is clonidine inthe form of clonidine hydrochloride or a mixture of clonidine base and ahydrochloride salt.
 13. A medical device of claim 8, wherein the medicaldevice is an implantable depot.
 14. A method of making a polymericmaterial, the method comprising mixing a plurality of biodegradablepolymers together to form a polymeric mixture, wherein the polymericmixture has a polydispersity from about 1.5 to about 2.5.
 15. A methodof claim 14, further comprising adding a solvent to the polymericmixture to form (i) a polymeric mixture solvent blend; or (ii) apolymeric mixture in solution.
 16. A method of claim 15 furthercomprising adding an anti-solvent to the polymeric mixture in solutionto separate a mixture of biodegradable polymers having (i)polydispersity from about 1.5 to about 2.5; or (ii) a polydispersitygreater than 2 from other polymers, co-monomers or monomers.
 17. Amethod of claim 13, wherein the solvent comprises n-hexane, cyclohexane,heptanes, methylene chloride, ethyl acetate, acetone or combinationsthereof.
 18. A method of claim 14, wherein the anti-solvent compriseswater ethanol, methanol, supercritical carbon dioxide, supercriticalnitrogen, supercritical water or mixtures thereof.
 19. A method of claim12, wherein the plurality of biodegradable polymers comprises a firstpolymer in an amount of about 10%, a second polymer in an amount ofabout 20%, a third polymer in an amount of about 50% and a fourthpolymer of about 20% by weight.
 20. A method for treating acute pain inan organism to reduce, prevent or treat pain, the method comprisingimplanting a depot comprising a plurality of biodegradable polymers, thepolymers having a polydispersity or molecular weight distribution fromabout 1.5 to about 2.5.